Determining when it is safe to fly a crew on a launch vehicle/spacecraft for the first time, especially when the test flight is a part of the overall system certification process, has long been a challenge for program decision makers. The decision on first flight is ultimately the judgment of the program and agency management in conjunction with the design and operations team. To aid in this decision process, a NASA team undertook the task to develop a generic framework for evaluating whether any given program or commercial provider has sufficiently complete and balanced plans in place to allow crewmembers to safely fly on human spaceflight systems for the first time. It was the team s goal to establish a generic framework that could easily be applied to any new system, although the system design and intended mission would require specific assessment. Historical data shows that there are multiple approaches that have been successful in first flight with crew. These approaches have always been tailored to the specific system design, mission objectives, and launch environment. Because specific approaches may vary significantly between different system designs and situations, prescriptive instructions or thorough checklists cannot be provided ahead of time. There are, however, certain general approaches that should be applied in thinking through the decision for first flight. This paper addresses some of the most important factors to consider when developing a new system or evaluating an existing system for whether or not it is safe to fly humans to/from space. In the simplest terms, it is time to fly crew for the first time when it is safe to do so and the benefit of the crewed flight is greater than the residual risk. This is rarely a straight-forward decision. The paper describes the need for experience, sound judgment, close involvement of the technical and management teams, and established decision processes. In addition, the underlying level of confidence the manager has in making the decision will also be discussed. By applying the outlined thought processes and approaches to a specific design, test program and mission objectives, a project team will be better able to focus the debate and discussion on critical areas for consideration and added scrutiny -- allowing decision makers to adequately address the first crewed flight decision.